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Updated: May 31, 2026
08:07
Single Molecule Fluorescence Energy Transfer Study of Ribosome Protein Synthesis
Published on: July 6, 2021
Mechanism of RACK1-dependent ZAKα activation at stalled and collided ribosomes
Anna Constance Vind1, José Francisco Martínez1, Zhenzhen Wu1
1Center for Gene Expression, Department of Cellular and Molecular Medicine, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen, Denmark.
Molecular Cell
|May 29, 2026
Summary
The ribotoxic stress response kinase ZAKα senses stalled ribosomes by binding their mRNA exit channel. This interaction activates ZAKα, initiating the cellular stress response.
Area of Science:
- Molecular Biology
- Cellular Biology
- Biochemistry
Background:
- The ribotoxic stress response (RSR) is crucial for cellular defense against stress.
- The upstream MAP3 kinase ZAKα activates the RSR, but its sensing mechanism for translational impairment is unclear.
Purpose of the Study:
- To elucidate how ZAKα senses translational impairment and initiates the RSR.
- To investigate the molecular interactions between ZAKα and ribosomes during stress.
Main Methods:
- Utilized AlphaFold3 for structural prediction.
- Employed RNA crosslinking and immunoprecipitation (CLIP) to identify ZAKα-RNA interactions.
- Investigated ZAKα binding to ribosomes in human cells.
Main Results:
- ZAKα directly binds to ribosomal proteins RACK1 and RPS27 and 18S rRNA helix-26.
- ZAKα spans the mRNA exit channel of elongating ribosomes.
- Ribosome stalling and collision stabilize ZAKα interaction, leading to kinase activation via dimerization and autophosphorylation.
Conclusions:
- ZAKα senses translational impairment by monitoring the ribosome mRNA exit channel.
- Stabilized ZAKα binding to stalled or collided ribosomes triggers RSR activation.
- Overlapping mechanisms involving RACK1 and ribosomal interactions mediate ZAKα activation.
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